Skin lightening agents, compositions and methods

ABSTRACT

Disclosed are coumarin derived compounds of formula I as skin lightening agents alone or in combination with other skin benefit agents and together with a cosmetic vehicle:  
                 
         Where each or both R 1  and/or R 2  represents hydrogen (H); linear or branched, saturated or unsaturated C 1 -C 12  alkyl, alkenyl, acyl, or heteroalkyl (preferably, alkoxy) groups; and    R 3  represents linear or branched, cyclic or acyclic, saturated or unsaturated C 1 -C 12  alkyl, alkenyl, cycloalkyl, cycloalkenyl, or heteroalkyl group; and    R 4  represents a hydrogen atom (H); straight or branched, cyclic or acyclic, saturated or unsaturated, containing or not containing a heteroatom C 1 -C 22  alkyl, alkenyl, cycloalkyl, cycloalkenyl, heteroalkyl, aryl, or heteroaryl group. In a most preferred embodiment, each R 1 , R 2  and R 4  represent H, while R 3  represents a methyl group, referred to herein as a 4-methyl 7-hydroxy-coumarin derivative, or coumarin derived resorcinol derivative, which may be prepared by catalytic (nickel or paladium catalyst) hydrogenation of 4-methyl 7-hydroxy-coumarin followed by hydrolysis. The inventive compounds, compositions and methods have effective skin lightening properties, may be less irritating to the skin, and are cost-effective and relatively simple to manufacture. Also disclosed are processes for making the inventive compounds of general formula I from 4-substituted-7-hydroxy coumarin derivatives.

FIELD OF THE INVENTION

The invention relates to coumarin derived compounds and cosmeticcompositions including same, and more specifically, 4-substituted7-hydroxy coumarin derived compounds, and their cosmetic use, such asskin lightening agents.

BACKGROUND OF THE INVENTION

Many people are concerned with the degree of pigmentation of their skin.For example, people with age spots or freckles may wish such pigmentedspots to be less pronounced. Others may wish to reduce the skindarkening caused by exposure to sunlight or to lighten their naturalskin color. To meet this need, many attempts have been made to developproducts that reduce the pigment production in the melanocytes. However,the substances identified thus far tend to have either low efficacy orundesirable side effects, such as, for example, toxicity or skinirritation. Therefore, there is a continuing need for new skinlightening agents, with improved overall effectiveness, as well asagents that lend themselves to ease of processing in their manufacture.

Resorcinol derivatives have cosmetic skin and hair benefits. Certainresorcinol derivatives, particularly 4-substituted resorcinolderivatives, are useful in cosmetic compositions for skin lighteningbenefits. Resorcinol derivatives are described in many publications,including U.S. Pat. No. 4,959,393; Hu et al., U.S. Pat. No. 6,132,740;Bradley, et al., U.S. Pat. No. 6,504,037; and Japanese published patentapplications JP 2001-010925 and JP2000-327557. Resorcinol derivativesare known compounds and can be readily obtained by various means,including by a method wherein a saturated carboxylic acid and resorcinolare condensed in the presence of zinc chloride and the resultantcondensate is reduced with zinc amalgam/hydrochloric acid (Lille, etal., Tr. Nauch-Issled. Inst. Slantsev 1969, No. 18:127-134), or by amethod wherein resorcinol and a corresponding alkyl alcohol are reactedin the presence of an alumina catalyst at a high temperature of from 200to 400° C. (British Patent No. 1,581,428). Skin lightening compoundsthat may be derived from coumarin are disclosed in Applicants'co-pending patent application Ser. No. 10/227,642 filed Aug. 23, 2002.Some of these compounds can be irritating to the skin.

Applicants have now discovered that the use of compounds that which maybe derived from coumarin derivatives (although not limited to suchprocess), deliver skin lightening benefits. The general chemicalformulas and structures of these compounds are discussed in more detailherein below. Hydroxy coumarin derived compounds, and especially4-substituted 7-hydroxy-coumarin derived compounds which resembleresorcinol derivatives, have been found to be effective and possiblyless irritating to the skin and are relatively simple to manufacture.These compounds are referred to herein as “coumarin derived resorcinolderivatives.” Coumarin derived resorcinol derivatives of the presentinvention have not been used for personal care or, in particular, forlightening skin.

SUMMARY OF THE INVENTION

Compounds of the general formula I and compositions including samedeliver cosmetic benefits, particularly skin lightening benefits, withpotential reduced irritation and relative ease of manufacture. Thepresent invention provides a cosmetic method of skin lightening using acomposition comprising in addition to a cosmetically acceptable vehicle,about 0.000001 to about 50% of a compound of formula I,

-   -   Where each or both R₁ and/or R₂ represents hydrogen (H); linear        or branched, saturated or unsaturated C₁- C₁₂ alkyl, alkenyl,        acyl, or heteroalkyl (e.g., preferably, alkoxy) groups.        Preferably, each or both R₁ and/or R₂ represents hydrogen (H);        linear or branched, saturated or unsaturated C₁- C₁₂ alkyl or        acyl groups. More preferably, both R₁ and R₂ represent hydrogen;        and    -   R₃ represents linear or branched, cyclic or acyclic, saturated        or unsaturated C₁-C₁₂ alkyl, alkenyl, cycloalkyl, cycloalkenyl,        or heteroalkyl group. Preferably, R₃ represents an alkyl group.        More preferably, R₃ represents a C₁ alkyl group (i.e, methyl        group); and    -   R₄ represents a hydrogen atom (H); straight or branched, cyclic        or acyclic, saturated or unsaturated; containing or not        containing a heteroatom (e.g. furans, dihydrofurans, pyrans)        C₁-C₂₂ alkyl, alkenyl, cycloalkyl, cycloalkenyl, heteroalkyl;        aryl, or heteroaryl group. Preferably, R₄ represents a hydrogen        atom (H); straight or branched, cyclic or acyclic, saturated or        unsaturated C₁-C₂₂ alkyl group. In a more preferred embodiment,        R₄ represents H.

In a most preferred embodiment, each R_(1,) R₂ and R₄ represent H, whileR₃ represents a methyl group, i.e. Compound of formula II herein.

These inventive 4-methyl 7-hydroxy-coumarin derived compounds, orcoumarin derived resorcinol derivatives, may be prepared by catalytic(nickel or paladium catalyst) hydrogenation of 4-substituted7-hydroxy-coumarin followed by hydrolysis. The hydroxy groups (where anyof R_(1,) R₂ and R₄ represents H) may be further substituted by methodsknown in the art, such as by esterification.

Further skin benefit agents may be included in the compositions andinventive method, such as alpha-hydroxy acids, beta-hydroxy acids,polyhydroxy acids, hydroquinone, t-butyl hydroquinone, Vitamin Cderivatives, dioic acids, retinoids, resorcinol derivatives, andmixtures thereof. Organic and inorganic sunscreens may also be included.

The inventive compositions and methods have effective skin lighteningproperties, may be less irritating to the skin, and are cost-effectiveand relatively simple to manufacture.

DETAILED DESCRIPTION OF THE INVENTION

The use of the inventive compounds that which may be derived fromcoumarin derivatives (although not limited to such process), deliverskin lightening benefits. The general chemical formulas and structuresof these compounds are discussed in more detail herein below. The4-substituted 7-hydroxy-coumarin derived compounds have been found to beeffective cosmetic agents, particularly, skin lightening agents, and arerelatively simple to produce.

As used herein, the term “cosmetic composition” is intended to describecompositions for topical application to human skin.

The term “skin” as used herein includes the skin on the face, neck,chest, back, arms, axilla, hands, legs, and scalp.

Except in the examples, or where otherwise explicitly indicated, allnumbers in this description indicating amounts of material or conditionsof reaction, physical properties of materials and/or use are to beunderstood as modified by the word “about”. All amounts are by weight ofthe composition, unless otherwise specified.

It should be noted that in specifying any range of concentration, anyparticular upper concentration can be associated with any particularlower concentration.

For the avoidance of doubt the word “comprising” is intended to meanincluding but not necessarily consisting of or composed of. Inotherwords the listed steps or options need not be exhaustive.

Skin Lightening Agents

The invention is concerned with compounds of general formula I, shownbelow, compositions including same, and their cosmetic use, particularlyas skin lightening agents. A particular advantage of the inventivecompositions and methods is that compounds of general formula I can beless irritating to the skin than other skin lightening compounds, eventhose with similar structure, and are relatively easy to manufacture:

-   -   Where each or both R₁ and/or R₂ represents hydrogen (H); linear        or branched, saturated or unsaturated C₁-C₁₂ alkyl, alkenyl,        acyl, or heteroalkyl (preferably, alkoxy) groups. Preferably,        each or both R₁ and/or R₂ represents hydrogen (H); linear or        branched, saturated or unsaturated C₁-C₁₂ alkyl or acyl groups.        More preferably, both R₁ and R₂ represent hydrogen; and    -   R₃ represents linear or branched, cyclic or acyclic, saturated        or unsaturated C₁-C₁₂ alkyl, alkenyl, cycloalkyl, cycloalkenyl,        or heteroalkyl group. Preferably, R₃ represents a C₁-C₁₂ alkyl        group, more preferably, a C₁ alkyl group (i.e, methyl group);        and    -   R₄ represents a hydrogen atom (H); straight or branched, cyclic        or acyclic, saturated or unsaturated, containing or not        containing a heteroatom (e.g. furans, dihydrofurans, pyrans)        C₁-C₂₂ alkyl, alkenyl, cycloalkyl, cycloalkenyl, heteroalkyl,        aryl, or heteroaryl group. Preferably, R₄ represents a hydrogen        atom (H); straight or branched, cyclic or acyclic, saturated or        unsaturated C₁-C₂₂ alkyl group. In a more preferred embodiment,        R₄ represents H.

In a most preferred embodiment, each R₁, R₂ and R₄ represent H, while R₃represents a methyl group. This most preferred embodiment is representedby compound of formula II:

-   -   Process. This most preferred embodiment, referred to herein as a        4-methyl 7-hydroxy-coumarin derived compound, or coumarin        derived resorcinol derivative, may be prepared by catalytic        (nickel or paladium catalyst, preferably Pd on carbon substrate,        i.e., Pd/C) hydrogenation of 4-methyl 7-hydroxy-coumarin        followed by hydrolysis. The hydroxy groups (where any of R_(1,)        R₂ and R₄ represents H) may be further substituted by methods        known in the art, such as by esterification. Other methods of        deriving the inventive compounds may also be available and the        invention is not limited by the method of preparation.

The compositions generally contain about 0.000001 to about 50% ofcoumarin derived compounds of general formula I. Compounds of formula IIare preferred. The amount of the coumarin derived compounds ispreferably in the range of about 0.00001% to about 10%, more preferablyabout 0.001 to about 7%, most preferably from 0.01 to about 5%, of thetotal amount of a cosmetic composition.

Further skin benefit agents may be included in the compositions usefulfor the inventive method. Organic and inorganic sunscreens may also beincluded.

The inventive compositions and methods have effective skin lighteningproperties, may be less irritating to the skin, and are cost-effectiveand relatively simple to manufacture.

Process Synthetic Procedures

I. Hydrogenation of 4-Substituted-7-hydroxycoumarins

General Procedure

A high pressure reaction vessel is charged with Compound of generalformula A, a 4-substituted-7-hydroxycoumarin (preferably,4-alkyl-7-hydroxy coumarin), in a suitable solvent (e.g., acetic acid,alcohol, organic solvents and mixtures thereof and a catalyst is added(e.g., homogeneous or heterogeneous catalysts such as Pd and/or Niattached to a suitable matrix and mixtures thereof. The reactor ispressurized with hydrogen (e.g., about 100 to about 800 psi) and stirredabove about 25° C. (e.g., about 25° C. to about 60° C.) until completeconsumption of 4-substituted-7-hydroxy coumarin (preferably,4-alkyl-7-hydroxy coumarin) is observed as monitored using a suitableanalytical method (e.g., TLC, GC, LC, hydrogen consumption, andcombinations thereof. The reaction mixture is filtered through aninsoluble support (e.g., celite, silica gel, and combinations thereof,the solvents removed under reduced pressure and the product purifiedusing purification methods such as, for example, re-crystallization,distillation, and combinations thereof.

Specific Procedure/Preferred Embodiment:7-hydroxy-3,4-dihydro-4-methylcoumarin (B1)

A Parr hydrogenator (1 L) was charged with 7-hydroxy-4-methylcoumarin,i.e., Compound of formula A1, (60 g, 0.34 mol) and acetic acid (350 ml).A suspension of 10% Pd/C (6.0 g) in acetic acid (150 ml) was added andthe reactor sealed, evacuated and purged with nitrogen (4×). The reactorwas pressurized to 320 psi with hydrogen and stirred at 30° C. for 16hr, at which point no hydrogen was consumed and TLC (4%methanol:chloroform) showed the clean formation of product at theexpense of starting material. The reactor was evacuated, purged withnitrogen and the mixture filtered through celite. The solvent wasremoved to give a white solid (60.5 g, 100%). Recrystallization fromethyl acetate:hexane afforded pure product as a white solid: m.p.109-110° C.; ¹H NMR (DMSO-d₆) d 1.19 (d, JJ=6.7, 3H), 2.52 (dd, JJ=15.9,7.3, 1H), 2.84 (dd, JJ=15.9, 5.5, 1H), 3.08 (m, 1H), 6.46 (d, JJ=2.4,1H), 6.58 (dd, JJ=8.2, 2.4, 1H), 7.10 (d, JJ=8.2, 1H), 9.66 (s, 1H); ¹³C(DMSO-d₆) d 19.84, 27.87, 36.45, 103.17, 111.38, 118.29, 127.17, 151.45,157.17, 168.11; m/z (EI; TMS derivatized; M⁺) 250; IR (neat; cm⁻¹)3379.6, 2969.2, 2930.2, 2871.5, 1748.0, 1630.7, 1601.4, 1518.4, 1454.89,1352.3, 1283.9, 1249.7, 1239.9, 1152.0, 1117.8, 1078.7, 1020.1, 995.7,942.0, 854.0, 814.9.II. Hydrolysis of 4-Substituted-3,4-dihydro-7-hydroxycoumarins

General Procedure

The Compound of general formula B, i.e.,4-substituted-3,4-dihydro-7-hydroxycoumarin, is suspended in water and ahydroxide ion equivalent reagent is added (e.g., sodium hydroxide,potassium hydroxide, polymer-bound carbonate, and combinations thereof.The reaction is monitored using a suitable analytical method (e.g., TLC,GC, LC, and combinations thereof until complete consumption of thestarting material. The reaction mixture is cooled down (e.g.,temperatures between about 0 and about 10° C.) and acidified with ahydrogen ion equivalent reagent (e.g., hydrochloric acid) until the pHof the solution reaches 1 or below. The solution is extracted with asuitable organic solvent (e.g., diethyl ether), the organic layer driedusing an insoluble drying agent (e.g., sodium sulfate), filtered and thesolvent removed. The product is purified using purification methods suchas, for example, re-crystallization, distillation, chromatography, orcombination thereof.

Specific Procedure/Preferred Embodiment: 3-(2,4-dihydroxyphenyl)-butyricacid (Compound of General Formula II)

Sodium hydroxide (5.0 M, 27 ml, 135 mmol) was added to a suspension of7-hydroxy-3,4-dihydro-4-methylcoumarin (Compound of formula B1) (8.0 g,45 mmol) in water (40 ml) at room temperature and the resulting solutionstirred for 20 min. At this time, TLC (4% methanol:chloroform) showedthe clean formation of product at the expense of starting material. Thesolution was cooled to 5° C. and carefully acidified with concentratedHCl to pH less than about 1, keeping the temperature at less than about15° C. throughout the addition. The solution was extracted with ethylether (4×100 ml), the organic layers washed with saturated NaCl (4×50ml), combined, dried (Na₂SO₄), filtered and the solvent removed to givea pale orange oil. Further purification by filtering through a short padof silica gel and eluting with ethyl acetate afforded pure product as awhite solid (8.3 g, 94%): m.p. 92-94° C.; ¹H NMR (DMSO-d₆) d 1.13 (d,JJ=7.0, 3H), 2.33 (dd, JJ=15.0, 8.9, 1H), 2.52 (dd, JJ=15.5, 7.3, 1H),3.32 (m, 1H), 6.16 (dd, JJ=8.2, 2.4, 1H), 6.28 (d, JJ=2.4, 1H), 6.84 (d,JJ=8.2, 1H), 9.08 (s, 1H), 9.59 (s, 1H), 11.87 (s, 1H); ¹³C NMR(DMSO-d₆) d 20.39, 28.97, 41.0, 102.58, 106.01, 122.55, 127.27, 155.19,156.18, 173.74; m/z (EI; TMS derivatized; M⁺) 412; IR (neat; cm⁻¹)3360.1, 2974.1, 2935.1, 2876.4, 1748.0, 1713.8, 1625.9, 1606.3, 1518.4,1459.8, 1381.6, 1347.4, 1283.9, 1254.6, 1239.9, 1156.9, 1117.8, 1025.0,981.0, 937.1, 849.1, 810.1.III. Esterification of 4-Substituted-3,4-dihydro-7-hydroxycoumarins

General Procedure

The Compound of general formula B, i.e.,4-substituted-3,4-dihydro-7-hydroxycoumarin, is dissolved in the alcoholof choice or, alternately, the coumarin and the alcohol are dissolved ina suitable solvent (e.g., tetrahydrofuran). An acid catalyst is added(e.g., sulfuric acid, acidic resin, or combinations thereof and thereaction is monitored using a suitable analytical method (e.g., TLC, GC,LC, or combinations thereof) until complete consumption of the startingmaterial. The reaction mixture is partly neutralized (to pH of about 4to about 7) with mild base (e.g., aqueous sodium bicarbonate) andpartitioned between a suitable organic solvent (e.g., diethyl ether) andwater. The organic layer is dried using an insoluble drying agent (e.g.,sodium sulfate), filtered and the solvent removed under reducedpressure. The product is purified using purification methods such as,for example, re-crystallization, distillation, chromatography, and/orcombinations thereof.

Specific Procedure/Preferred Embodiment: Methyl3-(2,4-dihydroxyphenyl)-butyrate (D1)

Concentrated sulfuric acid (1.2 mL, 43 mmol) was added to a solution of7-hydroxy-3,4-dihydro-4-methylcoumarin (B1) (75.8 g, 430 mmol) inmethanol (1 L) at room temperature and the solution stirred for about 16hours. At this time, TLC (8% methanol:chloroform) showed the cleanformation of product at the expense of starting material. The solutionwas neutralized with 7% NaHCO₃ solution (50 ml) and the majority of thesolvent (750 ml) removed under reduced pressure. The solution wasdiluted with ethyl acetate (1 L), washed successively with saturatedNaHCO₃: saturated NaCl (1:1, 200 ml), saturated NaCl (2×200 ml), dried(Na₂SO₄), filtered and the solvent removed to give an orange oil.Further purification by filtering through a short pad of silica gel andeluting with 5% methanol in chloroform afforded pure product as a paleorange gel (87 g, 98%): ¹H NMR (DMSO-d₆) d 1.13 (d, JJ=7.0, 3H), 2.42(dd, JJ=15.0, 8.9, 1H), 2.58 (dd, JJ=15.0, 5.8, 1H), 3.37 (m, 1H), 3.55(s, 3H), 6.15 (dd, JJ=8.6, 2.4, 1H), 6.28 (d, JJ=2.4, 1H), 6.84 (d,JJ=8.2, 1H), 8.93 (s, 1H), 9.11 (s, 1H); ¹³C NMR (DMSO-d₆) d 20.16,29.09, 40.77, 51.00, 102.55, 106.02, 122.09, 127.04, 155.18, 156.27,172.55; m/z (EI; TMS derivatized; M⁺) 354; IR (neat; cm⁻¹) 3384.5,2969.3, 1708.9, 1621.0, 1606.3, 1518.4, 1454.9, 1367.0, 1303.5, 1220.4,1166.7, 1108.1, 976.2, 839.4, 810.1.

Optional Skin Benefit Agents

Preferred cosmetic compositions are those suitable for the applicationto human skin according to the method of the present invention, whichoptionally, but preferably, include a skin benefit agent in addition tothe inventive coumarin derived compounds.

Suitable additional skin benefit agents include anti-aging,wrinkle-reducing, skin whitening, anti-acne, and sebum reduction agents.Examples of these include alpha-hydroxy acids, beta-hydroxy acids,polyhydroxy acids, hydroquinone, t-butyl hydroquinone, Vitamic Cderivatives, dioic acids, retinoids; betulinic acid; allantoin, aplacenta extract; and other resorcinol derivatives.

Cosmetically Acceptable Carrier

The cosmetically acceptable vehicle may act as a dilutant, dispersant orcarrier for the skin benefit ingredients in the composition, so as tofacilitate their distribution when the composition is applied to theskin.

The vehicle may be aqueous, anhydrous or an emulsion. Preferably, thecompositions are aqueous or an emulsion, especially water-in-oil oroil-in-water emulsion, preferentially oil in water emulsion. Water whenpresent will be in amounts which may range from 5 to 99%, preferablyfrom 20 to 70%, optimally between 40 and 70% by weight.

Besides water, relatively volatile solvents may also serve as carrierswithin compositions of the present invention. Most preferred aremonohydric C₁-C₃ alkanols. These include ethyl alcohol, methyl alcoholand isopropyl alcohol. The amount of monohydric alkanol may range from 1to 70%, preferably from 10 to 50%, optimally between 15 to 40% byweight.

Emollient materials may also serve as cosmetically acceptable carriers.These may be in the form of silicone oils and synthetic esters. Amountsof the emollients may range anywhere from 0.1 to 50%, preferably between1 and 20% by weight.

Silicone oils may be divided into the volatile and non-volatile variety.The term “volatile” as used herein refers to those materials which havea measurable vapor pressure at ambient temperature. Volatile siliconeoils are preferably chosen from cyclic or linear polydimethylsiloxanescontaining from 3 to 9, preferably from 4 to 5, silicon atoms. Linearvolatile silicone materials generally have viscosities less than about 5centistokes at 25° C. while cyclic materials typically have viscositiesof less than about 10 centistokes. Nonvolatile silicone oils useful asan emollient material include polyalkyl siloxanes, polyalkylarylsiloxanes and polyether siloxane copolymers. The essentiallynon-volatile polyalkyl siloxanes useful herein include, for example,polydimethyl siloxanes with viscosities of from about 5 to about 25million centistokes at 25° C. Among the preferred non-volatileemollients useful in the present compositions are the polydimethylsiloxanes having viscosities from about 10 to about 400 centistokes at25° C.

Among the ester emollients are:

-   -   (1) Alkenyl or alkyl esters of fatty acids having 10 to 20        carbon atoms. Examples thereof include isoarachidyl        neopentanoate, isononyl isonanonoate, oleyl myristate, oleyl        stearate, and oleyl oleate.    -   (2) Ether-esters such as fatty acid esters of ethoxylated fatty        alcohols.    -   (3) Polyhydric alcohol esters. Ethylene glycol mono and di-fatty        acid esters, diethylene glycol mono- and di-fatty acid esters,        polyethylene glycol (200-6000) mono- and di-fatty acid esters,        propylene glycol mono- and di-fatty acid esters, polypropylene        glycol 2000 monooleate, polypropylene glycol 2000 monostearate,        ethoxylated propylene glycol monostearate, glyceryl mono- and        di-fatty acid esters, polyglycerol poly-fatty esters,        ethoxylated glyceryl monostearate, 1,3-butylene glycol        monostearate, 1,3-butylene glycol distearate, polyoxyethylene        polyol fatty acid ester, sorbitan fatty acid esters, and        polyoxyethylene sorbitan fatty acid esters are satisfactory        polyhydric alcohol esters.    -   (4) Wax esters such as beeswax, spermaceti, myristyl myristate,        stearyl stearate and arachidyl behenate.    -   (5) Sterol esters, of which cholesterol fatty acid esters are        examples.

Fatty acids having from 10 to 30 carbon atoms may also be included ascosmetically acceptable carriers for compositions of this invention.Illustrative of this category are pelargonic, lauric, myristic,palmitic, stearic, isostearic, hydroxystearic, oleic, linoleic,ricinoleic, arachidic, behenic and erucic acids.

Humectants of the polyhydric alcohol-type may also be employed ascosmetically acceptable carriers in compositions of this invention. Thehumectant aids in increasing the effectiveness of the emollient, reducesscaling, stimulates removal of built-up scale and improves skin feel.Typical polyhydric alcohols include glycerol, polyalkylene glycols andmore preferably alkylene polyols and their derivatives, includingpropylene glycol, dipropylene glycol, polypropylene glycol, polyethyleneglycol and derivatives thereof, sorbitol, hydroxypropyl sorbitol,hexylene glycol, 1,3-butylene glycol, 1,2,6-hexanetriol, ethoxylatedglycerol, propoxylated glycerol and mixtures thereof. For best resultsthe humectant is preferably propylene glycol or sodium hyaluronate. Theamount of humectant may range anywhere from 0.5 to 30%, preferablybetween 1 and 15% by weight of the composition.

Thickeners may also be utilized as part of the cosmetically acceptablecarrier of compositions according to the present invention. Typicalthickeners include crosslinked acrylates (e.g. Carbopol 982),hydrophobically-modified acrylates (e.g. Carbopol 1382), cellulosicderivatives and natural gums. Among useful cellulosic derivatives aresodium carboxymethylcellulose, hydroxypropyl methylcellulose,hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose andhydroxymethyl cellulose. Natural gums suitable for the present inventioninclude guar, xanthan, sclerotium, carrageenan, pectin and combinationsof these gums. Amounts of the thickener may range from 0.0001 to 5%,usually from 0.001 to 1%, optimally from 0.01 to 0.5% by weight.

Collectively the water, solvents, silicones, esters, fatty acids,humectants and/or thickeners will constitute the cosmetically acceptablecarrier in amounts from 1 to 99.9%, preferably from 80 to 99% by weight.

An oil or oily material may be present, together with an emulsifier toprovide either a water-in-oil emulsion or an oil-in-water emulsion,depending largely on the average hydrophilic-lipophilic balance (HLB) ofthe emulsifier employed.

Surfactants may also be present in cosmetic compositions of the presentinvention. Total concentration of the surfactant will range from 0.1 to40%, preferably from 1 to 20%, optimally from 1 to 5% by weight of thecomposition. The surfactant may be selected from the group consisting ofanionic, nonionic, cationic and amphoteric actives. Particularlypreferred nonionic surfactants are those with a C₁₀-C₂₀ fatty alcohol oracid hydrophobe condensed with from 2 to 100 moles of ethylene oxide orpropylene oxide per mole of hydrophobe; C₂-C₁₀ alkyl phenols condensedwith from 2 to 20 moles of alkylene oxide; mono- and di-fatty acidesters of ethylene glycol; fatty acid monoglyceride; sorbitan, mono- anddi-C₈-C₂₀ fatty acids; block copolymers (ethylene oxide/propyleneoxide); and polyoxyethylene sorbitan as well as combinations thereof.Alkyl polyglycosides and saccharide fatty amides (e.g. methylgluconamides) are also suitable nonionic surfactants.

Preferred anionic surfactants include soap, alkyl ether sulfate andsulfonates, alkyl sulfates and sulfonates, alkylbenzene sulfonates,alkyl and dialkyl sulfosuccinates, C₈-C₂₀ acyl isethionates, acylglutamates, C₈-C₂₀ alkyl ether phosphates and combinations thereof.

Optional Components

In the cosmetic compositions of the invention, there may be optionallyadded plasticizers; calamine; antioxidants; chelating agents; as well assunscreens.

Other adjunct minor components may also be incorporated into thecosmetic compositions. These ingredients may include coloring agents,pigments, opacifiers, and perfumes. Amounts of these other adjunct minorcomponents may range anywhere from 0.001% up to 20% by weight of thecomposition.

Sunscreens. For use as sunscreen, metal oxides may be used alone or inmixture and/or in combination with organic sunscreens. Examples oforganic sunscreens include but are not limited those set forth in thetable below.

The amount of the organic sunscreens in the cosmetic composition ispreferably in the range of about 0.1 wt % to about 10 wt %, morepreferably about 1 wt % to 5 wt %. Preferred organic sunscreens arePARSOL MCX and Parsol 1789, due to their effectiveness and commercialavailability. TABLE 3 CTFA Name Trade Name Supplier Benzophenone-3UVINUL M-40 BASF Chemical Co. Benzophenone-4 UVINUL MS-40 BASF ChemicalCo. Benzophenone-8 SPECRA-SORB American Cyanamide UV-24 DEAMethoxycinnamate BERNEL HYDRO Bernel Chemical Ethyl dihydroxypropyl-AMERSCREEN P Amerchol Corp. PABA Glyceryl PABA NIPA G.M.P.A. Nipa Labs.Homosalate KEMESTER HMS Hunko Chemical Methyl anthranilate SUNAROME UVAFelton Worldwide Octocrylene UVINUL N-539 BASF Chemical Co. Octyldimethyl AMERSCOL Amerchol Corp. PABA Octyl PARSOL MCX Bernel Chemicalmethoxycinnamate Octyl salicylate SUNAROME Felton Worldwide WMO PABAPABA National Starch 2-Phenylbenzimidazole-5- EUSOLEX 232 EM Industriessulphonic acid TEA salicylate SUNAROME W Felton Worldwide3-(4-methylbenzylidene)- EUSOLEX 6300 EM Industries camphorBenzophenone-1 UVINUL 400 BASF Chemical Co. Benzophenone-2 UVINUL D-50BASF Chemical Co. Benzophenone-6 UVINUL D-49 BASF Chemical Co.Benzophenone-12 UVINUL 408 BASF Chemical Co. 4-Isopropyl dibenzoylEUSOLEX 8020 EM Industries methane Butyl methoxy dibenzoyl PARSOL 1789Givaudan Corp. methane Etocrylene UVINUL N-35 BASF Chemical Co.

Use of the Composition

The method according to the invention is intended primarily as using apersonal care product for topical application to human skin, as well asto lighten the skin, to reduce the degree of pigmentation in the skin,or to even the skin tone.

In use, a small quantity of the composition, for example from 1 to 5 ml,is applied to exposed areas of the skin, from a suitable container orapplicator and, if necessary, it is then spread over and/or rubbed intothe skin using the hand or fingers or a suitable device.

Product Form and Packaging

The cosmetic composition of the invention can be formulated as a lotionhaving a viscosity of from 4,000 to 10,000 mPas, a fluid cream having aviscosity of from 10,000 to 20, 000 mPas, or a cream having a viscosityof from 20,000 to 100,000 mPas or above. The composition can be packagedin a suitable container to suit its viscosity and intended use by theconsumer. For example, a lotion or fluid cream can be packaged in abottle or a roll-ball applicator or a propellant-driven aerosol deviceor a container fitted with a pump suitable for finger operation. Whenthe composition is a cream, it can simply be stored in a non-deformablebottle or squeeze container, such as a tube or a lidded jar. When thecomposition is a solid or semi-solid stick, it may be packaged in asuitable container for manually or mechanically pushing out or extrudingthe composition.

The invention accordingly also provides a closed container containing acosmetically acceptable composition as herein defined.

The following examples are by way of example, not by way of limitation,of the principles of the present invention, to illustrate the best modeof carrying out the invention.

EXAMPLE 1

The following compounds were used throughout the examples that follow.These compounds were prepared in accordance with the procedures setforth in this Example 1.

The compound of formula A1, referred to herein as 4-methyl 7-hydroxycoumarin was used as a starting material to prepare the coumarin derivedresorcinol compounds according to the present invention.

EXAMPLE 2

Cosmetic compositions within the scope of the invention were prepared.

A base formulation shown in the Table below was made by heating phase Aingredients to 70 to 85° C. with stirring. Phase B ingredients wereheated in a separate container to 70 to 85° C. with stirring. Then,phase A was added into phase B while both phases were kept at 70 to 85°C. The mixture was stirred for at least 15 minutes at 70 to 85° C., thencooled. TABLE 4 a b Ingredients % wt. % wt. Phase Isostearyl Palmitate6.00 6.00 A C12-C15 Alkyl Octanoate 3.00 3.00 A PEG-100 Stearate 2.002.00 A Glyceryl Hydroxystearate 1.50 1.50 A Stearyl Alcohol 1.50 1.50 AStearic acid 3.00 4.00 A TEA, 99% 1.20 1.20 B Dimethicone 1.00 1.00 ASorbitan Monostearate 1.00 1.00 A Magnesium Aluminum Silicate 0.60 0.60B Vitamin E acetate 0.10 0.10 A Cholesterol 0.50 0.50 A Simethicone 0.010.01 B Xanthan gum 0.20 0.20 B Hydroxyethylcellulose 0.50 0.50 BPropylparaben 0.10 0.10 B Disodium EDTA 0.05 0.05 B Butylatedhydroxytolene 0.05 0.05 B Compound of formula II 0.05 2.00 B Niacinamide1.00 1.00 B Metal oxide 2.50 5.00 B Methylparaben 0.15 0.15 B Water BAL*BAL* B Total 100.00 100.00 B*BAL means Balance.

EXAMPLE 3

Additional cosmetic compositions within the scope of the invention wereprepared. TABLE 5 Component Wt % Phase water, DI BALANCE A disodium EDTA0.05 A magnesium aluminum silicate 0.6 A methyl paraben 0.15 Asimethicone 0.01 A butylene glycol 1,3 3.0 A hydroxyethylcellulose 0.5 Aglycerine, USP 2.0 A xanthan gum 0.2 A triethanolamine 1.2 B stearicacid 3.0 B propyl paraben NF 0.1 B glyceryl hydroxystearate 1.5 Bstearyl alcohol 1.5 B isostearyl palmitate 6.0 B C12-15 alcoholsoctanoate 3.0 B dimethicone 1.0 B cholesterol NF 0.5 B sorbitan stearate1.0 B Micronized titanium dioxide 5.0 C tocopheryl acetate 0.1 B PEG-100stearate 2.0 B sodium stearoyl lactylate 0.5 B hydroxycaprylic acid 0.1C Compound of formula II 10.0 C PARSOL MCX 2.4 C alpha-bisabolol 0.2 C

The composition of Example 3, was prepared as follows:

-   -   1. Heat Phase A to 80° C.    -   2. Heat Phase B to 75° C. in a separate container    -   3. Add B to A and mix with heat off for 30 min.    -   4. At 50° C. add Phase C and mix for 10 min.

EXAMPLES 4-11

A set of additional compositions useful in the methods of the presentinvention were prepared within the scope of the present invention andare listed in the table below. TABLE 6 Examples (wt. %) 4 acidIngredients Phase soap base 5 6 7 8 9 10 11 Stearic acid A 17.9 17.917.9 17.9 17.9 17.9 17.9 17.9 Sodium cetearyl A 2.2 1 1.5 2 3 2 sulfate*(emulsifier) Myrj 59* A 2 2 2 2 2 1 (emulsifier) Span 60* A 2 2 2 2 2 1(emulsifiers) Compound of B 0.05 0.05 2.0 2.0 3.5 3.5 5.0 10.0 formulaII Micronized Zinc B 2.50 5.00 5.00 2.50 2.50 5.00 2.50 5.00 Oxide KOH,22% (form in 2.20 situ soap with stearic acid) Octyl 2.50 2.50 2.50 2.50methoxycinnamate Water B BAL BAL BAL BAL BAL BAL BAL BAL Glycerin B 1 11 1 1 1 1 1

EXAMPLE 12 Cell Based Assay

This example shows the skin lightening effect of using 4-methyl7-hydroxy-coumarin derived resorcinol compounds as skin lighteningagents in accordance with the inventive method. This experiment wascarried out using a cell based assay.

B16 mouse melanoma cells were utilized in the following experiment toevaluate the efficacy of skin lightening agents. B16 cells were platedin 96-well microtiter plates at a density of 5000 cells per well andcultured overnight in Dulbecco's Modified Eagle's Medium (phenol redfree) containing 10% fetal bovine serum and 1% penicillin/streptomycinat 37° C. in the presence of 5% CO₂. After 24 hours, the medium wasreplaced with fresh growth medium containing the treatments. Allcultures were incubated for 72 hours at which time melanin was visiblein the control treatment. The melanin-containing medium was transferredto a clean 96-well plate and quantified by reading the absorbency at530-nm. Cell viability was assessed by measurement of lactatedehydrogenase levels to ensure the decrease in melanin was not a resultof cellular toxicity. TABLE 7 Compound % of Control (Skin LighteningAgent) Concentration (Melanin Synthesis) 7-hydroxy-3,4-dihydro- 6.25micromolar 75.8% 4-methylcoumarin (B1) 4-Ethyl Resorcinol 6.25micromolar 34.0% 3-(2,4-dihydroxyphenyl)- 6.25 micromolar 32.8% butyricacid (II) Methyl 3-(2,4- 6.25 micromolar 36.4% dihydroxyphenyl)-butyrate (D1)

From the results tabulated above it appears that coumarin derivedresorcinol compounds of the present invention reduce melanin synthesisto about the same degree than 4-ethyl resorcinol.

EXAMPLE 13 Mushroom Tyrosinase Assay

Mushroom tyrosinase inhibition is indicative of reduction in melaninsynthesis, thereby showing skin lightening effect. This experiment showsthe efficacy of coumarin derived resorcinol derivatives of the presentinvention.

Into each well of a 96-well plate, 150 microliters of phosphate buffer(100 mM, pH 7.0), 10 microliters of L-DOPA (L-3,4-Dihydroxyphenylalanine, 10 mM), and 20 microliters of skin lighteningagent (dissolved in ethanol, which is the control) were added. Followingan initial measurement of background absorbency at 475-nm, 20microliters of mushroom tyrosinase (Sigma T-7755; 6050 units/ml) wasadded and incubated at room temperature.

Absorbency was read at 475-nm over the following time points: 0, 2, 4,and 6.5 minutes. The data is plotted as 475-nm absorbency vs. time(minutes) and the slope of the line is calculated (ΔAbs 475 nm/min).Values are expressed as the percentage of the respective untreatedethanol control reaction.${\%\quad{of}\quad{Control}} = {\frac{\left( {{Reaction}\quad{rate}\quad{for}\quad{treated}\quad{reaction}} \right)}{\left( {{Reaction}\quad{rate}\quad{for}\quad{untreated}\quad{control}} \right)} \times 100\%}$TABLE 8 % of Control Compound Concentration (Melanin Synthesis) 4-EthylResorcinol  0.1 micro-M 72.7   1 micro-M 46.3   10 micro-M 30.8  100micro-M 20.7 7-Hydroxy Coumarin  0.1 micro-M 104   1 micro-M 100   10micro-M 108  100 micro-M 117 7-hydroxy-3,4-dihydro-   1 micro-M 94.24-methylcoumarin (B1) 1.56 micro-M 90.4 12.5 micro-M 70.4  100 micro-M75.3 3-(2,4-dihydroxyphenyl)-   1 micro-M 73.3 butyric acid (II) 1.56micro-M 41.6 12.5 micro-M 28.0  100 micro-M 20.6 Methyl 3-(2,4-   1micro-M 73.1 dihydroxyphenyl)- 1.56 micro-M 39.3 butyrate (D1) 12.5micro-M 35.8  100 micro-M 41.0

The data show that the coumarin derived compounds of formulas II and D1are substantially as effective as 4-ethyl resorcinol, both compoundshaving good skin lightening effects. The7-hydroxy-3,4-dihydro-4-methylcoumarin (B1) compound from which thecompounds of the present invention may be derived is not effective inskin lightening, as measured by the mushroom tyrosinase assay.

EXAMPLE 14

This example illustrates an inventive process according to the presentinvention. R-groups are as previously defined hereinabove.

It should be understood that the specific forms of the invention hereinillustrated and described are intended to be representative only.Changes, including but not limited to those suggested in thisspecification, may be made in the illustrated embodiments withoutdeparting from the clear teachings of the disclosure. Accordingly,reference should be made to the following appended claims in determiningthe full scope of the invention.

1. A cosmetic method of skin lightening comprising applying to the skina composition comprising: a. about 0.000001 to about 50% of a compoundof general formula I

Where each or both R₁ and/or R₂ represents hydrogen (H); linear orbranched, saturated or unsaturated C₁-C₁₂ alkyl, alkenyl, acyl, orheteroalkyl groups; R₃ represents linear or branched, cyclic or acyclic,saturated or unsaturated C₁-C₁₂ alkyl, alkenyl, cycloalkyl,cycloalkenyl, or heteroalkyl group; R₄ represents a hydrogen atom (H);straight or branched, cyclic or acyclic, saturated or unsaturated,containing or not containing a heteroatom C₁-C₂₂ alkyl, alkenyl,cycloalkyl, cycloalkenyl, heteroalkyl, aryl, or heteroaryl group; and b.a cosmetically acceptable carrier.
 2. The method of claim 1, whereinsaid composition further comprises a sunscreen.
 3. The method of claim2, wherein said sunscreen is a micronized metal oxide.
 4. The method ofclaim 1, wherein said compound is a 4-methyl 7-hydroxy coumarin derivedresorcinol derivative.
 5. The method of claim 1, wherein said compoundis a compound of formula II:


6. The cosmetic method of claim 1, wherein R₁ and R₂ both representhydrogen.
 7. The cosmetic method according to claim 1, wherein saidcomposition further comprises a skin benefit agent selected from thegroup consisting of alpha-hydroxy acids, beta-hydroxy acids, polyhydroxyacids, hydroquinone, t-butyl hydroquinone, Vitamin C derivatives, dioicacids, retinoids, resorcinol derivatives, and mixtures thereof.
 8. Thecosmetic method of claim 1, wherein said composition further comprisesan organic sunscreen selected from the group consisting ofBenzophenone-3, Benzophenone-4, Benzophenone-8, DEA, Methoxycinnamate,Ethyl dihydroxypropyl-PABA,-Glyceryl PABA, Homosalate, Methylanthranilate, Octocrylene, Octyl dimethyl PABA, Octyl methoxycinnamate(PARSOL MCX), Octyl salicylate, PABA, 2-Phenylbenzimidazole-5-sulphonicacid, TEA salicylate, 3-(4-methylbenzylidene)-camphor, Benzophenone-1,Benzophenone-2, Benzophenone-6, Benzophenone-12, 4-Isopropyl dibenzoylmethane, Butyl methoxy dibenzoyl methane (PARSOL 1789), Etocrylene, andmixtures thereof.
 9. A cosmetic composition comprising: a. about0.000001 to about 50% of a compound of general formula I:

wherein each or both R₁ and/or R₂ represents hydrogen (H); linear orbranched, saturated or unsaturated C₁- C₁₂ alkyl, alkenyl, acyl, orheteroalkyl groups; R₃ represents linear or branched, cyclic or acyclic,saturated or unsaturated C₁-C₁₂ alkyl, alkenyl, cycloalkyl,cycloalkenyl, or heteroalkyl group; R₄ represents a hydrogen atom (H);straight or branched, cyclic or acyclic, saturated or unsaturated,containing or not containing a heteroatom C₁-C₂₂ alkyl, alkenyl,cycloalkyl, cycloalkenyl, heteroalkyl, aryl, or heteroaryl group; and b.a cosmetically acceptable carrier.
 10. The cosmetic composition of claim9, wherein said compound is a compound of formula II:


11. The cosmetic composition of claim 9, wherein R₁ and R₂ bothrepresent hydrogen.
 12. The cosmetic composition of claim 9, whereinsaid compound comprises about 0.00001% to about 10% of said composition.13. The cosmetic composition of claim 9, wherein said compound comprisesabout 0.001% to about 7% of said composition.
 14. The cosmeticcomposition of claim 9, wherein said compound comprises about 0.01% toabout 5% of said composition.
 15. A process for making compounds havinga general formula selected from the group consisting of B, C, D, andmixtures thereof, comprising:

wherein R₃ represents linear or branched, cyclic or acyclic, saturatedor unsaturated C₁-C₁₂ alkyl, alkenyl, cycloalkyl, cycloalkenyl, orheteroalkyl group; R₄ represents a hydrogen atom (H); straight orbranched, cyclic or acyclic, saturated or unsaturated, containing or notcontaining a heteroatom C₁-C₂₂ alkyl, alkenyl, cycloalkyl, cycloalkenyl,heteroalkyl, aryl, or heteroaryl group.
 16. The process of claim 15further comprising substitution of the 1,3-hydroxy positions of thephenyl ring to yield compound of general formula I:

wherein each or both R₁ and/or R₂ represents hydrogen (H); linear orbranched, saturated or unsaturated C₁- C₁₂ alkyl, alkenyl, acyl, orheteroalkyl groups.
 17. A compound of general formula I

Where each or both R₁ and/or R₂ represents hydrogen (H); linear orbranched, saturated or unsaturated C₁-C₁₂ alkyl, alkenyl, acyl, orheteroalkyl groups; R₃ represents linear or branched, cyclic or acyclic,saturated or unsaturated C₁-C₁₂ alkyl, alkenyl, cycloalkyl,cycloalkenyl, or heteroalkyl group; R₄ represents a hydrogen atom (H);straight or branched, cyclic or acyclic, saturated or unsaturated,containing or not containing a heteroatom C₁-C₂₂ alkyl, alkenyl,cycloalkyl, cycloalkenyl, heteroalkyl, aryl, or heteroaryl group. 18.The compound of claim 17, wherein said compound is a compound of formulaII:


19. The compound of claim 1, wherein said compound is a 4-methyl7-hydroxy coumarin derived resorcinol derivative.
 20. The compound ofclaim 1, wherein R₁ and R₂ both represent hydrogen.